The long-term objective of this Project is the localization and characterization of genes important for Tourette's syndrome (TS) and related conditions. Recent research has led to several advances in our understanding of TS and related conditions: 1) there is a greater range of phenotypic expression for TS, 2) TS and related disorders are much more common than had previously been thought, 3) there appear to be genes of major effect important for the manifestation of this condition, and 4) a genome screen using affected sib-pairs suggests that there are at least two regions that may harbor susceptibility loci for TS. The prevalence of TS and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of TS and associated behaviors will be of direct benefit to patients concerned about recurrence in their families. Ultimately, clarifying the genetics of this condition may elucidate its pathogenesis. Previous studies completed under the auspices of this program project suggest that the mode of transmission of TS and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of TS. Previous linkage studies of TS employing large multigenerational families have been unsuccessful in locating genes important for the expression of the disorder. Thus, during the previous funding period, we undertook an affected sib-pair genetic linkage study of TS as part of an international consortium. A genome-wide screen was completed using highly polymorphic markers 10 cM apart, and two highly suggestive genomic regions were identified. In the current application, we are proposing to collect 100 additional affected sib-pair and 260 triads (an affected individual and his/her parents) to follow up these initial results. We will also follow up all results in a sample of 5 large multigenerational families that have been studied for the past decade. Phenotypic data will be obtained by direct structured psychiatric interview of all pertinent family members with respect to the occurrence of TS and related conditions using expert interviewers trained by the Clinical Core. In conjunction with the Data Analytic Core, linkage disequilibrium studies will be utilized to more accurately localize and identify genes of interest. Linkage and association analyses will be completed with state-of-the-art non-parametric methods. Ultimately, knowledge of vulnerability genotypes will enrich the structural and functional brain imaging data obtained in Projects; the stereological data obtained in one Project; the immunological data obtained in Projects; and the treatment response data being collected in another Project.